Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named "cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase II") provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
The references below that disclose antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel pyridines disclosed herein are such safe and also effective antiinflammatory agents furthering such efforts. The invention's compounds are found to show usefulness i vivo as antiinflammatory agents with minimal side effects. The substituted pyridinyl compounds disclosed herein preferably selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
Pyridines have been described for various uses, including the treatment of inflammation. U.S. Pat. No. 5,225,418 to Miller, describes 4-(1H)-quinolinones as intermediates in the preparation of antiinflammatory agents.
European Application, EP388,619, published Sep. 26, 1990, describes a method of preparing pyridine-2,3-dicarboxylic acids.
European Application, EP308,020, published Mar. 22, 1989, describes 1,2-dihydro-2-oxo-3-pyridylcarboxylic acids as having antibiotic activity. 5-(4-Fluorophenyl)-1,2-dihydro-6-4-(methylsulfonyl)phenyl!-2-oxo-pyridyl- 3-carboxylic acid is specifically described.
U.S. Pat. No. 3,655,679, to Shen et al, describes aryl pyridine carboxylic acids as having antiinflammatory activity.
British Pat. No. 1,238,959 describes pyridyl derivatives as having antiinflammatory activity. Specifically, 4-(2-1H-pyridon-3-yl)benzenesulfonamide is described.
U.S. Pat. No. 4,011,328, to Pinhas et al, describes derivatives of pyridine-3-acetic acid as having antiinflammatory properties. Specifically, 5-(4-fluorophenyl)-6-4-(methylthio)phenyl!-2-methyl-3-pyri dyl!acetic acid is described. U.S. Pat. No. 4,533,666, to Matsumoto et al, describes 6-phenyl-2,3-(4-methoxyphenyl)pyridine derivatives as having antiinflammatory properties.
The invention's pyridyl compounds are found to show usefulness in vivo as antiinflammatory agents with minimal side effects.